Recently completed studies suggest that intraportally injected 125I-labeled insulin is rapidly internalized and concentrated in rat liver microsomes. The time courses of appearance and disappearance of trichloroacetic acid preciptable radioactivity in plasma membranes and microsomes further suggest, although do not prove, that insulin binds to plasma membranes before it is internalized. They also provide presumptive evidence suggesting that the sequential degradative pathway is operative in vivo. Current studies have been designed to explore the significance of these observations in greater depth. To this end studies are in progress to identify the specific component(s) of the microsomal fractions that are involved in the binding of 125I-insulin, the binding and dissociation kinetics of 125I-insulin to these structures both in vivo and in vitro as compared to plasma membranes, and the specificity of the subcellular disposition processes for insulin. Studies are planned to investigate possible control factors that may be involved in the disposition of 125I insulin as well as possible actions of 125I-insulin in the microsomes. Studies are also planned in normal human, obese and maturity-onset diabetic subjects that are designed to estimate the metabolic half-life of intravenously injected 125I-insulin and related peptides and to attempt to define the role of the liver in the involved processes. The proposed studies would add significantly to our understanding of glucose:insulin homeostasis in the liver and possible derangements in diabetes melitus. Their importance lies in the fact that the liver is probably the most sensitive target of insulin action and the major organ involved in its degradation.